Patricia A. Cowan

Conversion to sirolimus in solid organ transplantation: a Single-Center experience

BACKGROUND Calcineurin inhibitors are associated with adverse events, including nephrotoxicity and diabetes that might reduce the benefits of long-term graft survival. We report our experience in converting kidney (K), kidney-pancreas (KP), pancreas (P), and (L) recipients from a calcineurin inhibitor/mycophenolate mofetil (MMF)/prednisone dose-induced nephrotoxicity (K = 9, KP = 5, P = 1, L = 5), hemolytic uremic syndrome (HUS) (K = 7, KP = 5), chronic allograft nephropathy (K = 12, L = 1), and glucose intolerance (K = 9, KP = 6, P = 2, L = 2). METHODS The conversion protocol consisted of an abrupt discontinuation of the calcineurin inhibitor with sirolimus (8-12 mg, PO loading dose) initiated 24-72 hours after stopping the calcineurin inhibitor. Sirolimus was titrated to target trough levels of 12-16 ng/mL. Daclizumab 2 mg/kg IV was given to all KP and P recipients on days 0 and 14 postconversion. RESULTS Resolution of HUS occurred in 12 of 12 patients (100%) with a drop in serum creatinine from 3.3 +/- 1.5 to 1.8 +/- 0.9 mg/dL (P =.04). Sirolimus conversion due to nephrotoxicity, HUS, and chronic allograft nephropathy improved serum creatinine from 2.9 +/- 1.4 to 2.2 +/- 0.9 mg/dL (P =.01). Eleven of 19 patients (58%) resolved glucose intolerance. Two patients suffered rejection due to noncompliance. Increases in cholesterol (208 +/- 70 to 243 +/- 77 mg/dL, P <.05) and triglycerides (232 +/- 145 to 265 +/- 148 mg/dL, P = NS), and minimal reduction in platelet values (243 +/- 85 to 237 +/- 85, P = NS) occurred. CONCLUSIONS These data suggest that a calcineurin inhibitor-free immunosuppressive regimen with sirolimus, mycophenolate mofetil, and steroids preserves graft function in patients with clinical indications warranting calcineurin inhibitor discontinuation.

Suppression of insulin secretion is associated with weight loss and altered macronutrient intake and preference in a subset of obese adults

PURPOSE: Hyperinsulinemia is a common feature of many obesity syndromes. We investigated whether suppression of insulin secretion, without dietary or exercise intervention, could promote weight loss and alter food intake and preference in obese adults.METHODS: Suppression of insulin secretion was achieved using octreotide-LAR 40 mg IM q28d for 24 weeks in 44 severely obese adults (89% female, 39% minority). Oral glucose tolerance testing was performed before and after treatment, indices of β-cell activity (CIRgp), insulin sensitivity (CISI), and clearance (CP/I AUC) were computed, and leptin levels, 3-day food records and carbohydrate-craving measurements were obtained. DEXA evaluations were performed pre- and post-therapy in an evaluable subgroup.RESULTS: For the entire cohort, significant insulin suppression was achieved with simultaneous improvements in insulin sensitivity, weight loss, and body mass index (BMI). Leptin, fat mass, total caloric intake, and carbohydrate craving significantly decreased. When grouped by BMI response, high responders (HR; ΔBMI<−3 kg/m2) and low responders (LR; ΔBMI between −3 and −0.5) exhibited higher suppression of CIRgp and IAUC than nonresponders (NR; ΔBMI−0.5). CISI improved and significant declines in leptin and fat mass occurred only in HR and LR. Conversely, both leptin and fat mass increased in NR. Carbohydrate intake was markedly suppressed in HR only, while carbohydrate-craving scores decreased in HR and LR. For the entire cohort, ΔBMI correlated with ΔCISI, Δfat mass, and Δleptin. ΔFat mass also correlated with ΔIAUC and ΔCISI.CONCLUSIONS: In a subcohort of obese adults, suppression of insulin secretion was associated with loss of body weight and fat mass and with concomitant modulation of caloric intake and macronutrient preference.

Racial differences in glucagon-like peptide-1 (GLP-1) concentrations and insulin dynamics during oral glucose tolerance test in obese subjects

Obese African-American (AA) subjects have higher resting and stimulated insulin concentrations than obese Caucasians (C), which could not be explained by the severity of obesity or the degree of insulin sensitivity. We investigated whether differences in glucagon-like peptide-1 (GLP-1), the most potent incretin that regulates insulin secretion, might explain racial differences in insulin response. Accordingly, we measured fasting and stimulated glucose, insulin, and GLP-1 levels during a 3-h oral glucose tolerance test (OGTT) in 26 obese C (age 38±2 y, body mass index 44±1 kg/m2) and 16 obese AA (age 36±2 y, BMI 46±2 kg/m2) subjects. Corrected insulin response (CIR30), a measure of β-cell activity, whole body insulin sensitivity index (WBISI), and area under the curve (AUC) for insulin, GLP-1, and C-peptide/insulin ratio were computed from the OGTT.Glucose levels, fasting and during the OGTT, were similar between racial groups; 32% of the C and 31% of the AA subjects had impaired glucose tolerance. With a similar WBISI, AAs had significantly higher CIR30 (2.3±0.4 vs 1.01±0.1), insulin response (IAUC: 23 974±4828 vs 14 478±1463), and lower insulin clearance (0.07±0.01 vs 0.11±0.01) than C (all, P<0.01). Obese AAs also had higher fasting GLP-1 (6.7±2.5 vs 4.5±1.1) and GLP-1AUC (1174.7±412 vs 822.4±191) than C (both, P<0.02). Our results indicate that obese AAs had higher concentrations of GLP-1 both at fasting and during the OGTT than obese C. The increased GLP-1 concentration could explain the greater insulin concentration and the increased prevalence of hyperinsulinemia-associated disorders including obesity and type 2 diabetes in AAs.

Effects of ingesting protein with various forms of carbohydrate following resistance-exercise on substrate availability and markers of anabolism, catabolism, and immunity

BackgroundIngestion of carbohydrate (CHO) and protein (PRO) following intense exercise has been reported to increase insulin levels, optimize glycogen resynthesis, enhance PRO synthesis, and lessen the immuno-suppressive effects of intense exercise. Since different forms of CHO have varying glycemic effects, the purpose of this study was to determine whether the type of CHO ingested with PRO following resistance-exercise affects blood glucose availability and insulin levels, markers of anabolism and catabolism, and/or general immune markers.Methods40 resistance-trained subjects performed a standardized resistance training workout and then ingested in a double blind and randomized manner 40 g of whey PRO with 120 g of sucrose (S), honey powder (H), or maltodextrin (M). A non-supplemented control group (C) was also evaluated. Blood samples were collected prior to and following exercise as well as 30, 60, 90, and 120 min after ingestion of the supplements. Data were analyzed by repeated measures ANOVA or ANCOVA using baseline values as a covariate if necessary.ResultsGlucose concentration 30 min following ingestion showed the H group (7.12 ± 0.2 mmol/L) to be greater than S (5.53 ± 0.6 mmol/L; p < 0.03); M (6.02 ± 0.8 mmol/L; p < 0.05), and C (5.44 ± 0.18 mmol/L; p < 0.0002) groups. No significant differences were observed among groups in glucose area under the curve (AUC) values, although the H group showed a trend versus control (p = 0.06). Insulin response for each treatment was significant by time (p < 0.0001), treatment (p < 0.0001) and AUC (p < 0.0001). 30-min peak post-feeding insulin for S (136.2 ± 15.6 u IU/mL), H (150.1 ± 25.39 u IU/mL), and M (154.8 ± 18.9 u IU/mL) were greater than C (8.7 ± 2.9 u IU/mL) as was AUC with no significant differences observed among types of CHO. No significant group × time effects were observed among groups in testosterone, cortisol, the ratio of testosterone to cortisol, muscle and liver enzymes, or general markers of immunity.ConclusionCHO and PRO ingestion following exercise significantly influences glucose and insulin concentrations. Although some trends were observed suggesting that H maintained blood glucose levels to a better degree, no significant differences were observed among types of CHO ingested on insulin levels. These findings suggest that each of these forms of CHO can serve as effective sources of CHO to ingest with PRO in and attempt to promote post-exercise anabolic responses.

The effect of isolation methods and the use of different enzymes on islet yield and in vivo function

The ability to isolate high-yield pure and viable islets from human cadaver pancreas donors is dependent on donor factor as well as isolation factors. The aim of this study was to examine factors influencing islets recovery and in vivo function with an emphasis on donor and isolation methods as well as to compare the effectiveness of Liberase, widely used in clinical islet isolation, with Serva for the isolation of pure functional islets. The results of 123 islet isolations using Liberase for digestion were compared with those of 113 isolations with Serva. Islet equivalents per gram of tissue were similar between Liberase and Serva (3620 ± 1858 vs. 4132 ± 2104, p < 0.2) as well as the percent purity (75 ± 16 vs. 74 ± 15, p < 0.9). In vivo function of islets from 71 isolations (Liberase = 45, Serva = 26) were further tested by transplantation into NOD-SCID mice following short-term culture (<6 days, n = 71). Our data show that both Liberase- and Serva-isolated islets showed similar function results following short-term culture. These data demonstrate that there is no difference in islet yield, purity, and function between the two enzymes. However, when these 71 isolations were analyzed for in vivo function with emphasis on donor factors, cold ischemia time (12.0 ± 5.3 vs. 15.0 ± 5.7, p < 0.04), islet integrity (1.6 ± 0.7 vs. 1.3 ± 0.5, p < 0.05), and female gender were the only factors that correlated with in vivo function. We also compared the mechanical-shaking method for islets isolation with hand-shaking methods. Our results show that although there is no different in islet yield, purity, and integrity between different enzymes using the same method, hand-shaking method yields more islets with better integrity than mechanical-shaking method.

Review: Obesity and cardiometabolic syndrome in children:

The cardiometabolic syndrome is highly prevalent among overweight youth. The risk of developing the cardiometabolic syndrome is likely triggered or exacerbated by concurrent obesity, unhealthy lifestyle/eating habits, and hormonal changes (puberty). Current screening recommendations include measurement of blood pressure, fasting insulin and glucose, and total cholesterol. However, limiting assessments to these measures underestimates cardiometabolic risk in overweight youth, particularly minorities. Early identification of cardiometabolic risk in its incipient stages may justify early and more aggressive intervention to prevent progression and complications. This review provides rationale for additional assessments to determine cardiometabolic risk in overweight youth and recommends treatment options.

Effects of lifestyle intervention and metformin on weight management and markers of metabolic syndrome in obese adolescents.

Purpose: The purposes of this study are threefold: to determine what components of the metabolic syndrome are present in obese adolescents, to determine what differences exist in the effects of lifestyle intervention versus lifestyle intervention plus metformin on weight management and select markers of metabolic syndrome in obese adolescents, and to determine which factors predict weight loss in obese adolescents treated with lifestyle changes and metformin. Data sources: The study was a secondary data analysis utilizing a retrospective chart review of 63 obese adolescents aged 11 through 18 who were treated for obesity at the LeBonheur Youth Lifestyle Clinic from January 1, 2000, through June 30, 2005. Lifestyle interventions included diet, exercise, and counseling. The medication utilized was metformin. Outcomes evaluated included body mass index, relative body mass index (RBMI), weight, waist and hip circumference, blood pressure, serum lipid levels, fasting plasma glucose, 2‐h oral glucose tolerance tests, and insulin levels. Changes in mean values between groups were evaluated using the General Linear Models procedure. Logistic regression was utilized to determine which factors might predict weight loss. Conclusions: The metformin group (N= 37) tended to be heavier, older, and had more components of the metabolic syndrome than the nonmetformin group (N= 26). All components of the metabolic syndrome were present in both groups (overall prevalence 55%). Both groups had a downward trend in RBMI, a surrogate marker for weight loss, but only the metformin group had a significant loss in RBMI points from baseline to end. There was a trend toward better diastolic blood pressure at 6 months in the metformin group (p= 0.06), which was not seen in the nonmetformin group. The only predictors of weight loss were higher RBMI (those who were heavier lost more) and the absence of type 2 diabetes mellitus (type 2 DM) (those with type 2 DM were less likely to lose 10 or more points in RBMI). Implications for practice: All components of the metabolic syndrome are present in obese adolescents. The use of lifestyle changes and lifestyle changes plus metformin both produce some degree of weight loss, but subjects on metformin in this study lost significantly more RBMI points than those on lifestyle changes alone. Subjects with type 2 DM are less likely to lose weight than those without type 2 DM. Larger studies and studies with subjects more representative of the general population need to be carried out to assist in the development of evidence‐based practice guidelines.

Race affects insulin and GLP-1 secretion and response to a long-acting somatostatin analogue in obese adults.

OBJECTIVE: This study investigated (1) the effect of octreotide-LAR (Sandostatin-LAR®Depot; Novartis) on the enteroinsular axis in a biracial cohort of severely obese adults, (2) whether octreotide suppression of insulin secretion occurs by both a direct β-cell effect and through mediating a glucagon-like peptide 1 (GLP-1) response, and (3) whether differences in GLP-1 concentrations could explain racial differences in insulin concentrations.DESIGN: Prospective, open-label trial using a pre–post test design.SETTING: Single university, clinical research center.SUBJECTS: In all, 42 healthy, severely obese Caucasian and African-American (AA) adults (93% female, 64% Caucasian, age=37.8±1.2 y, weight=123±4.2 kg, BMI=44.5±1 kg/m2), recruited through physician referral and newspaper ads, participated in the study.INTERVENTIONS: Indices of β-cell activity, insulin and GLP-1 response before and during a 75-gm oral glucose tolerance test were determined before and after 24 weeks of octreotide-LAR.RESULTS: AA exhibited higher β-cell activity, and insulin and GLP-1 concentrations than Caucasians. Octreotide-LAR suppressed the insulin and GLP-1 levels in both groups.

Characterizing dietary intake and physical activity affecting weight gain in kidney transplant recipients

Context— Weight gain after kidney transplantation affects 50% to 90% of kidney transplant recipients. Factors leading to weight gain in recipients are thought to include a change in lifestyle (eg, dietary intake and physical activity), age, race, sex, and immunosuppressant medications. Objective— To examine dietary intake and physical activity of kidney transplant recipients at baseline and 3 and 6 months after transplantation to identify contributing factors to weight gain. Design— Descriptive, correlational study using secondary data from a larger parent study examining genetic and environmental contributors to weight gain after kidney transplantation. Participants and Setting— Forty-four kidney transplant recipients at a mid-South university hospital-based transplant institute who had dietary intake, physical activity, and clinical data at baseline and 3 and 6 months were included. Main Outcome Measures— Dietary intake, physical activity, weight, and body mass index. Results— Mean weight gain increased by 6% from baseline to 6 months. Interestingly, dietary intake did not change significantly from baseline to 6 months. Hours of sleep per day decreased during the same period (P = .02). Dietary intake, physical activity, age, race, sex, and immunosuppression showed no significant relationship to weight gain at 6 months. Conclusion— Little consideration has been given to dietary intake and physical activity of kidney transplant recipients and the effects of these variables on weight gain. Further studies with a larger sample are needed, as weight gain after transplantation is a significant risk factor for diminished long-term outcomes.

Self-efficacy, physical activity, and aerobic fitness in middle school children: Examination of a pedometer intervention program

Physical activity in children has been associated with a number of health benefits. Unfortunately, physical inactivity continues to increase. The purpose of this study was to examine the relationships among self-efficacy levels, physical activity, aerobic fitness, and body composition (relative body mass index [RBMI]) and to determine whether a school-based pedometer intervention program would improve those variables. The sample consisted of 116 rural 11- to 13-year-old students. Weakly positive correlations between self-efficacy, physical activity, and aerobic fitness and weakly correlated inverse relationships between self-efficacy, physical activity, aerobic fitness and RBMI were found. There was no statistical significance between the intervention and control group when analyzing outcome variables. These findings suggest that those with optimal RBMI levels have higher self-efficacy, physical activity and aerobic fitness levels. Although not statistically significant, the intervention group had greater improvements in mean self-efficacy scores, aerobic fitness levels, and RBMI.